ORGANIC LETTERS
Efficient Syntheses of Heterocycles and Carbocycles by Electrophilic Cyclization of Acetylenic Aldehydes and Ketones
2004 Vol. 6, No. 10 1581-1584
Dawei Yue, Nicola Della Ca`, and Richard C. Larock* Department of Chemistry, Iowa State UniVersity, Ames, Iowa 50011
[email protected] Received February 21, 2004
ABSTRACT
Highly substituted oxygen heterocycles can be prepared in good yields at room temperature by reacting o-(1-alkynyl)-substituted arene carbonyl compounds with NBS, I2, ICl, p-O2NC6H4SCl, or PhSeBr and various alcohols or carbon-based nucleophiles. Naphthyl ketones and iodides are readily prepared by the reaction of 2-(1-alkynyl)arene-carboxaldehydes with I2 and simple olefins or alkynes.
The electrophilic cyclization of functionally substituted alkenes has provided an extremely useful route for the synthesis of a wide variety of heterocyclic and carbocyclic compounds, which have often proven to be useful as intermediates in the synthesis of natural products and pharmaceuticals.1 The analogous chemistry of alkynes has been far less studied, although it would appear to be a very promising route to an extraordinary range of useful, functionally substituted heterocycles and carbocycles.2 Our recent work has indicated that benzothiophenes,3 isoquinolines,4 and isocoumarins5 can be easily synthesized by the electrophilic cyclization of appropriate functionally substituted alkynes using iodine-, sulfur-, and selenium-containing electrophiles under exceptionally mild reaction conditions. Others have recently reported a number of very useful analogous iodinepromoted cyclizations of functionally substituted alkynes.6 (1) (a) Lotagawa, O.; Inoue, T.; Taguchi, T. ReV. Heteroatom Chem. 1996, 15, 243. (b) Frederickson, M.; Grigg, R. Org. Prep. Proc. Int. 1997, 29, 33. (c) Cardillo, G.; Orena, M. Tetrahedron 1990, 46, 3321. (2) (a) Drenth, W. In Chemistry of Triple-Bonded Functional Groups; Patai, S., Ed.; J. Wiley: Chichester, UK, 1994; Vol. 2, pp 873-915. (b) Schmid, G. H. In The Chemistry of the Carbon-Carbon Triple Bond; Patai, S., Ed.; J. Wiley: Chichester, UK, 1978; Vol. 1, pp 275-341. (3) Yue, D.; Larock, R. C. J. Org. Chem. 2002, 67, 1905. (4) Huang, Q.; Hunter, J. A.; Larock, R. C. J. Org. Chem. 2002, 67, 3437. (5) Yao, T.; Larock, R. C. Tetrahedron Lett. 2002, 43, 7401. 10.1021/ol049690s CCC: $27.50 Published on Web 04/13/2004
© 2004 American Chemical Society
Recently, Yamamoto reported an interesting cyclization of acetylenic aldehydes to 1-alkoxy-1H-isochromenes catalyzed by palladium.7 The Pd(II) salt employed was claimed to exhibit a dual role as both a Lewis acid and a transitionmetal catalyst. In a more recent study, the analogous preparation of 1H-isochromenes has been achieved upon reaction of bis(pyridine) iodonium tetrafluoroborate (IPy2BF4) and HBF4 with the same acetylenic carbonyl precursors in the presence of various nucleophiles.8 The use of expensive (6) (a) Barluenga, J.; Trincado, M.; Rubio, E.; Gonza’lez, J. M. Angew. Chem., Int. Ed. 2003, 42, 2406. (b) Knight, D. W.; Redfern, A. L.; Gilmore, J. J. Chem. Soc., Perkin Trans. 1 2002, 622. (c) Arcadi, A.; Cacchi, S.; Giuseppe, S. D.; Fabrizi, G.; Marinelli, F. Org. Lett. 2002, 4, 2409. (d) Bellina, F.; Biagetti, M.; Carpita, A.; Rossi, R. Tetrahedron Lett. 2001, 42, 2859. (e) Bellina, F.; Biagetti, M.; Carpita, A.; Rossi, R. Tetrahedron 2001, 57, 2857. (f) Flynn, B. L.; Verdier-Pinard, P.; Hamel, E. Org. Lett. 2001, 5, 651. (g) Djuardi, E.; McNelis, E. Tetrahedron Lett. 1999, 40, 7193. (h) Marshall, J. A.; Yanik, M. M. J. Org. Chem. 1999, 64, 3798. (i) Arcadi, A.; Cacchi, S.; Fabrizi, G.; Marinelli, F.; Moro, L. Synlett 1999, 1432. (j) Knight, D. W.; Redfern, A. L.; Gilmore, J. J. Chem. Soc., Chem. Commun. 1998, 2207. (k) Redfern, A. L.; Gilmore, J. Synlett 1998, 731. (l) Ren, X.F.; Konaklieva, M. I.; Shi, H.; Dicy, H.; Lim, D. V.; Gonzales, J.; Turos, E. J. Org. Chem. 1998, 63, 8898. (m) Bew, S. P.; Knight, D. W. J. Chem. Soc., Chem. Commun. 1996, 1007. (n) El-Taeb, G. M. M.; Evans, A. B.; Jones, S.; Knight, D. W. Tetrahedron Lett. 2001, 42, 5945. (7) (a) Asao, N.; Nogami, T.; Takahashi, K.; Yamamoto, Y. J. Am. Chem. Soc. 2002, 124, 764. (b) Nakamura, H.; Ohtaka, M.; Yamamoto, Y. Tetrahedron Lett. 2002, 43, 7631. (8) Barluenga, J.; Vazquez-Villa, H.; Ballesteros, A.; Gonzalez, J. M. J. Am. Chem. Soc. 2003, 125, 9028.
Scheme 1
IPy2BF4, together with B(OMe)3 or HBF4, and the relatively complicated stepwise procedure employed make this approach a bit unwieldy synthetically. Furthermore, the scope of this cyclization has yet to be reported. We simultaneously found that this three-component reaction9 proceeds smoothly by using various electrophiles such as I2, ICl, NBS, p-O2NC6H4SCl, and PhSeBr to generate the corresponding iodine-, bromine-, sulfur-, and seleniumsubstituted heterocycles in high yields under very mild reaction conditions. Herein, we wish to report a more convenient and efficient approach to these types of heterocycles involving electrophilic cyclization using a range of electrophiles and nucleophiles. Our initial studies were aimed at finding optimal reaction conditions for the electrophilic cyclization of the o-(1alkynyl)benzaldehydes. Our investigation began with the reaction of o-(phenylethynyl)benzaldehyde (1), methanol, and I2 (Scheme 1). The reaction was first attempted using 0.25 mmol of o-(phenylethynyl)-benzaldehyde (1), 1.2 equiv of methanol, 1 equiv of K2CO3, and 1.2 equiv of I2 in CH2Cl2 at room temperature. Iodocyclization proceeded smoothly and provided an 88% yield of the desired isochromene product 2. Other solvents such as CH3CN and DMF were also investigated and proved to be far less effective. KHCO3 and NEt3 were also investigated as bases. While KHCO3 provided a slightly lower yield of the desired product than K2CO3, NEt3 proved to be ineffective and none of the desired product was detected. Although CH2Cl2 is not a good solvent for K2CO3, the presence of K2CO3 was crucial for a clean, high-yielding reaction. K2CO3 is presumed to neutralize the byproduct HI of the electrophilic cyclization, which can also react with the acetylenic aldehyde and generate the corresponding pyrilium salt.10 The use of methanol as the reaction solvent resulted in a lower yield. Use of 1.2 equiv of I2 has proven to be sufficient to achieve a high yield. Further increasing the amount of I2 did not give better yields. (9) For a recent review on multicomponent reactions, see, for instance: Do¨mling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168. (10) Tovar, J. D.; Swager, T. M. J. Org. Chem. 1999, 64, 6499. 1582
Based on the above optimization efforts, the combination of 1.2 equiv of nucleophile, 1 equiv of K2CO3, 1.2 equiv of I2, and the use of CH2Cl2 as the solvent at room temperature gave the best results. This procedure has been used as our standard reaction conditions for subsequent electrophilic cyclizations. To test the generality of this chemistry, acetylenic aldehydes bearing different substituents on the carboncarbon triple bond were synthesized in high yields by the palladium/copper-catalyzed coupling of o-bromobenzaldehyde and the corresponding terminal alkynes.11 The resulting acetylenic aldehydes were then allowed to react under our standard electrophilic cyclization conditions to afford the corresponding 1H-isochromene products in good to excellent yields. The results are summarized in Table 1. Alkynes bearing an aromatic ring, as well as alkyl and vinylic substituents, all react well with methanol, n-butanol, and 2-iodobenzyl alcohol to provide the desired iodocyclization products in very good yields (entries 1-3, 8, and 11). Interestingly, not only alcohols but also an electron-rich aromatic compound like N,N-dimethylaniline can be used as a nucleophile, affording iodocyclization products in generally good to excellent yields (entries 4, 9, and 12). Pyridine derivative 16 readily reacted under our standard conditions using I2 or ICl and provided the desired iodocyclization product in a 64% yield (entries 13 and 14). In all cases, reactions with readily available, inexpensive iodine gave higher yields of isochromene product than the Barluenga process, which used the expensive iodonium salt and HBF4 (compare Barluenga’s results in parentheses with ours). To further explore the scope of this cyclization, NBS was also used and provided a decent yield of the desired cyclization product (entry 5). Commercially available sulfur and selenium electrophiles have also been employed in this process and have been found to provide very good yields of the desired cyclization products using methanol as the nucleophile (entries 6, 7, and 10). The reactions with p-O2NC6H4SCl were complete in a shorter period of time and gave higher yields of products than those with PhSeBr. R-Acetylenic aryl ketones are also viable substrates for cyclization (see entry 15). It should be noted, however, that ketone 18 reacted smoothly with I2 to provide a 90% yield of the 5-exo-dig cyclization product 19, rather than the sixmembered ring ether formed by the electrophilic cyclization of benzaldehyde derivatives. The use of K2CO3 again provides very mild basic conditions and avoids the acidinitiated, partial decomposition of this cyclization product described in Barluenga’s publication.8 Interestingly, when we followed the stepwise procedure described in Barluenga’s paper, we were unable to get high yields of the desired iodocyclization products. Instead, an unreactive solid, presumed to be the pyrilium salt, was generated. On the basis of this observation, a possible mechanism is proposed in Scheme 2. We believe that these cyclizations proceed by anti attack of the electrophile and (11) (a) Sonogashira, K. In Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., Stang, P. J., Eds.; Wiley-VCH: Weinheim, 1998; Chapter 5, pp 203-229. (b) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 4467. Org. Lett., Vol. 6, No. 10, 2004
Table 1. Electrophilic Cyclization of Acetylenic Aldehydes, Imines, and Ketonesa
a All reactions were run under the following conditions, unless otherwise specified. To a solution of 2.5 mL of CH Cl containing 0.25 mmol of the 2 2 alkyne, 0.30 mmol of the nucleophile, and 0.25 mmol of K2CO3 was added 0.30 mmol of electrophile under stirring, and the resulting mixture was further stirred at room temperature for the desired time. b Barluenga’s yields are reported in parentheses. c Reaction was run on a 1.0 mmol scale; the 0.25 mmol scale reaction provides an 88% yield of compound 2.
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Scheme 2
the carbonyl to produce a pyrilium intermediate. Before it forms an insoluble precipitate,10 the pyrilium intermediate is immediately trapped by the nucleophile present in the reaction mixture. Our study has also shown that substituted naphthalenes can be synthesized in high yields by using alkenes or alkynes as the trapping reagent12 (Scheme 3) and that the use of the
again, the use of readily available, easily handled I2 greatly simplifies the procedure developed by Barluenga. We believe that this approach to carbo- and heterocycles should prove to be quite useful in synthesis, particularly when one considers that there are many ways to transform the resulting halogen, sulfur, and selenium functional groups into other substituents. For instance, the resulting heterocyclic iodides should be particularly useful intermediates in many palladium-catalyzed processes such as Sonogashira,11 Suzuki,13 and Stille14 cross-couplings and Heck reactions.15 Acknowledgment. We gratefully acknowledge the National Science Foundation and the donors of the Petroleum Research Fund, administered by the American Chemical Society, for partial support of this research. Supporting Information Available: Experimental procedures and characterization data for all starting materials and products. This material is available free of charge via the Internet at http://pubs.acs.org. OL049690S
Scheme 3
more sophisticated iodonium reagent IPy2BF4 employed by Barluenga12b for this same process is not necessary. Once
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(12) (a) Asao, N.; Takahashi, K.; Lee, S.; Kasahara, T.; Yamamoto, Y. J. Am. Chem. Soc. 2002, 124, 12650. (b) Asao, N.; Nogami, T.; Lee, S.; Yamamoto, Y. J. Am. Chem. Soc. 2003, 125, 10921. (c) Asao, N.; Kasahara, T.; Yamamoto, Y. Angew. Chem., Int. Ed. 2003, 42, 3504. (d) Barluenga, J.; Vazquez-Villa, H.; Ballesteros, A.; Gonzalez, J. M. Org. Lett. 2003, 5, 4121. (13) (a) Suzuki, A. J. Organomet. Chem. 1999, 576, 147. (b) LloydWilliams, P.; Giralt, E. Chem. Soc. ReV. 2001, 30, 145. (c) Suzuki, A. In Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., Stang, P. J., Eds.; Wiley-VCH: Weinheim, 1998; pp 49-97. (d) Miyaura, N. Chem. ReV. 1995, 95, 2457. (14) (a) Negishi, E.; Dumond, Y. Handbook of Organopalladium Chemistry for Organic Synthesis; 2002; Vol. 1, p 767. (b) Kosugi, M.; Fugami, K. Handbook of Organopalladium Chemistry for Organic Synthesis; 2002; Vol. 1, p 263. (c) Kosugi, M.; Fugami, K. J. Organomet. Chem. 2002, 653, 50. (15) (a) Crisp, G. T. Chem. Soc. ReV. 1998, 27, 427. (b) Brase, S.; De Meijere, A. In Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., Stang, P. J., Eds.; Wiley-VCH: Weinheim, 1998; pp 99-166. (c) Palladium Reagents in Organic Synthesis; Heck, R. F., Ed.; Academic Press: San Diego, 1985; pp 276-287.
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